Paternal valproate use and impact of shared genetic susceptibility on child neurodevelopment.

This study looked at whether fathers taking valproate (an epilepsy medication) pass on higher genetic risks for autism, ADHD, or epilepsy to their children. Researchers found that fathers taking valproate had higher genetic risk scores for epilepsy than fathers taking other medications. However, they didn't find clear evidence that these genetic factors or the medications themselves affected children's actual development. The study suggests that genetic factors shared between parents and children may explain some previously reported risks.

This Norwegian cohort study examined whether fathers' genetic makeup influences the previously reported association between paternal valproate use and neurodevelopmental disorders in children. Researchers analyzed genetic risk scores for epilepsy, ADHD, and autism in fathers with epilepsy using different medications (n=158) compared to healthy controls (n=54,752). Fathers using valproate had significantly higher genetic risk scores for epilepsy than those using other medications or controls. However, no robust associations were found between paternal medication use or genetic risk and actual child neurodevelopmental outcomes.

The study identified significant genetic overlap between epilepsy, ADHD, and autism risk factors, suggesting shared biological pathways and highlighting the importance of considering genetic confounding in medication safety research.

Results suggest that genetic factors may confound associations between paternal valproate use and child neurodevelopmental risks. Clinicians should consider family genetic history when counseling about medication risks during conception planning. Further research needed to clarify causal relationships.

Small sample sizes for medication groups (37-80 participants). Study design unclear from abstract. Genetic risk scores may not capture all relevant genetic factors. Limited assessment of child neurodevelopmental outcomes methodology not detailed.

Paternal use of valproate during spermatogenesis has been associated with increased risk of neurodevelopmental disorders (NDDs) in offspring, yet the role of genetic confounding is unclear. Using data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), we assessed genetic susceptibility to epilepsy, ADHD and autism spectrum disorders (ASD) in fathers with epilepsy treated with valproate (n = 41), lamotrigine or levetiracetam (n = 37), other anti-seizure medications (ASMs; n = 80), and healthy controls (n = 54,752). Fathers using valproate had significantly higher polygenic risk scores (PRSs) for epilepsy compared to those using lamotrigine or levetiracetam (mean difference: 0.66, 95% CI: 0.21-1.11, p ≈ 0.005), other ASMs (0.41, 95% CI: 0.02-0.81, p ≈ 0.04) and controls (0.85, 95% CI: 0.54-1.15, p = 5.8 × 10⁻⁸). No robust associations were found between paternal ASM use or epilepsy PRS and child neurodevelopmental outcomes.

Significant genetic overlap was found among the top 1% of weighted SNPs in the PRSs for epilepsy, ADHD and ASD (428 genes, p ≈ 0.0001), enriched for neurodevelopmental pathways. These results emphasize the importance of considering shared genetic susceptibility when assessing risks of paternal valproate exposure.